Jerrold J. Heindel PhDScientific Program Administrator

National Institute of Environmental Health SciencesNational Institutes of Health/DHHS

heindelj@niehs.nih.gov

Developmental and Environmental Origins of Obesity: A Bad Start

Lasts a Lifetime

1999

Obesity Trends* Among U.S. AdultsBRFSS, 1990, 1999, 2008

(*BMI 30, or about 30 lbs. overweight for 5’4” person)

2008

1990

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Why Do We Care About Obesity??Why Do We Care About Obesity??

Health Health RisksRisks

Hypertension•Cardiovascular diseases

Caronary artery diseasesStroke

•Many forms of cancerendometrialprostatebreastcolon

•Reproductive disease

•PCOS

•Liver disease

•Fatty liver

•Gallbladder disease

•Respiratory disease

•Sleep disorders

•Arthritis

•Edema

•Dislipidemia

•Type II diabetesInsulin resistanceGlucose intolerance

Proposed Causes of ObesityProposed Causes of Obesity

• Genetic factors• Environmental factors (nutrition, exercise)• Psychological factors

– Stress– Lack of sleep

• Illness (hypothyroidism, Cushing’s syndrome)• Drugs (steroids, antidiabetic, antidepressants)• Viruses (adenovirus 36)

• Environmental Chemicals

Current ParadigmCurrent Paradigm

• Focus is on Genetics• Obese at birth or at age 6-10….obese as adult• Some people eat and don’t gain weight• It can’t be only due to genetic mutations….timing!• All diseases have both genetic and environmental component!

• Focus is on treatment• Reduce food intake and increase exercise• Highly intractable (90% regain wt in a year) suggesting a “set point”• Programming a “set point” occurs during development

• Current approaches are not working…

Developmental Origins of Disease: Developmental Origins of Disease: Altered Developmental Programming Lead to Disease Throughout Life Altered Developmental Programming Lead to Disease Throughout Life

A bad start…lasts a lifetime!It is likely that all non

infectious complex diseases have their origins during

development.

Stages of Prenatal and Postnatal Organ DevelopmentStages of Prenatal and Postnatal Organ Development

Central nervous system (3wks - 20 years)Central nervous system (3wks - 20 years)

Ear (4-20 wks)Ear (4-20 wks)

Kidneys (4-40 wks)Kidneys (4-40 wks)

Heart (3-8)Heart (3-8)

Immune system (8-40 wks; competence & memory birth-10yrs)Immune system (8-40 wks; competence & memory birth-10yrs)

Adipose tissueAdipose tissue

Lungs (3-40 wks; alveoli birth-10yrs)Lungs (3-40 wks; alveoli birth-10yrs)

Reproductive system (7-40wks; maturation in puberty)Reproductive system (7-40wks; maturation in puberty)

Skeleton (1-12 wks)Skeleton (1-12 wks)

Source: Altshuler, K; Berg, M et al. Critical Periods in Development, OCHP Paper Series on Children's Health and the Environment, February 2003.

Developmental Origin of Adult Disease: Developmental Origin of Adult Disease: Barker HypothesisBarker Hypothesis

• 1989 David Barker: inverse relationship b/w birth weight and death from heart disease in England and Wales

• “Dutch Hunger Winter”: food supply to the Netherlands was cut off by Nazis

• Individuals born during this time had increased insulin-resistance as adults

D. Barker, Trends in Endocrinology and Met. (2010)

Fetal Origin of Adult Disease (FEBAD) confirmed for:

• Coronary heart disease• Hypertension• Type II diabetes/obesity

Developmental Origins of Obesity: Role of Nutrition in Developmental Origins of Obesity: Role of Nutrition in HumansHumans

• Low birth weight (due to nutritional deficiency) results in increased incidence of adult obesity if there is catch-up growth in first few years of life.

• Excess Weight gain first 6 months: fat that lasts forever.

• Breastfeeding for 4-6 months is protective against childhood obesity.

• High birth weight….increased incidence of adult obesity.

– Overweight mothers

– Gestational diabetes

Transgenerational Transgenerational ObesityObesity

Waterland et al, Int J Obesity 2008

In a population with a genetic tendency for obesity, effects of maternal obesity accumulate over successive generations to shift the population distribution toward increased adult body weight, and suggest that epigenetic mechanisms are involved in this process.

Endocrine Control of Development and Tissue Endocrine Control of Development and Tissue FunctionsFunctions

• Estrogens

• Androgens

• Thyroid

• Others– Steroid – Glucocorticoid, Vit D, etc.

– Non-Steroid – Prolactin, Insulin, etc.

– Non-Classical Hormones – Vit A, etc.

Some Chemicals Disrupt the Endocrine System

“Endocrine Disruptors”

Exogenous agents that interfere with the production, release, transport, metabolism, binding, action, or elimination of the natural hormones

…a “new” type of toxicity

Active at environmentally relevant doses (ppb)

Conservation of hormone receptors and pathways across species!

HERBICIDES2,4,-D2,4,5,-TAlachlorAmitroleAtrazineLinuronMetribuzinNitrofenTrifluralin

FUNGICIDESBenomylEthylene thioureaFenarimolHexachlorobenzeneMancozebManebMetiram - complexTri-butyl-tinVinclozolinZineb

METALS

INSECTICIDESAldicarbbeta-HCHCarbarylChlordaneChlordeconeDBCPDicofolDieldrinDDT and metabolitesEndosulfanHeptachlor / H-epoxideLindane (gamma-HCH)MalathionMethomylMethoxychlorOxychlordaneParathionSynthetic pyrethroidsTransnonachlorToxaphene

INDUSTRIAL CHEMICALSBisphenol - A PolycarbonatesButylhydroxyanisole (BHA)CadmiumChloro- & Bromo-diphenylDioxinsFuransLeadManganeseMethyl mercuryNonylphenolOctylphenolPBDEsPCBsPentachlorophenolPenta- to NonylphenolsPerchloratePFOAp-tert-PentylphenolPhthalatesStyreneTestosterone synthesis inhibitor Estrogen receptor agonist

Thyroid hormone disruptor Androgen receptor antagonist

Endocrine Disrupting Chemicals

Developmentally-Induced Diseases (Human)• Pulmonocardiovascular

– Asthma (Air Pollution)

– Heart disease/hypertension (BPA)

– Stroke (PCBs)

• Brain/Nervous System

– Alzheimer's disease (Lead)

– Parkinson’s disease (Pesticides)

– ADHD/learning disabilities (PCBs, Lead, Ethanol, Organochlorine Pesticides)

• Reproductive/Endocrine– Breast/prostate cancer (BPA)– Endometriosis (Dioxin, PCBs)– Infertility (Phthalates,

Estrogens, Pesticides)– Diabetes/metabolic

syndrome (BPA)– Early Puberty (Estrogens, BPA)– Obesity (BPA, Tributyl Tin,

Organochlorine Pesticides)

• Immune/Autoimmune

– Susceptibility to infections (Dioxin)

– Autoimmune Disease (Dioxin)

Why are There Sensitive Windows and Why are There Sensitive Windows and Persistent effects?Persistent effects?

A Paradigm Shift in ToxicologyEpigenetics

•Modifications of DNA and chromatin which can be heritable and affect genome function (transcription, replication, recombination, but don’t affect DNA backbone

•Controls cell and tissue differentiation

Developmental Programming: EpigeneticsDevelopmental Programming: Epigenetics• The effects of developmental exposures, persist because they

alter epigenetic signaling, which lasts throughout life

– DNA methylation of CpG islands or “shores”

– Chromatin changes/remodeling

– siRNA

• The developmental time period is the most sensitive to epigenetic alterations…when tissues are forming.

Normal Stem Cell

CG CG

CG CG

Normal Growth and Development

CG CG

CG CG

CH3

Hormones

Disease/Dysfunction

Altered Gene Expression persists

Abnormal Growth & Development

EDCs

EDCs

Changes in DNA methylation pattern CG CG

CG CG

CH3

CH3

Epigenetic/Environmental Basis of DiseaseEpigenetic/Environmental Basis of Disease

Epigenetics(stable but plastic)

Genetic polymorphisms(born with)

Inter-individual variability

Environmental Stressors

Susceptibility to Disease, Toxicants, Drugs, Altered behavior

(Chemicals, diet, drugs,

stress, infections)

Both Genetics and Epigenetics Control Our HealthBoth Genetics and Epigenetics Control Our Health

Shuk mei Ho

Developmental Basis of Disease: ObesityDevelopmental Basis of Disease: Obesity• Are there data indicating that obesity has its origins during

development…and do environmental chemicals exposures play a role?

Endocrine system controls metabolism/weight and is therefore sensitive to disruption by endocrine disrupting

chemicals leading to obesity.

Obesity: Due to Disruption of the Endocrine SystemObesity: Due to Disruption of the Endocrine System

Badman and Flier science 2005

Metabolic Set Point Programmed by Chemical Metabolic Set Point Programmed by Chemical Exposures During DevelopmentExposures During Development

Hypothesis: Developmental chemical exposures may induce metabolic shifts that alter regulation of energy balance weight gain

Weight gain Weight loss

Altered Programming↑↑ SusceptibilityCertainly food intake and exercise are important but

environmental chemicals can alter the “setpoint” for gaining weight…how much food it takes to put on

weight…. and also how much exercise is needed to reduce weight.

The Developmental Basis of Obesity: Obesogen The Developmental Basis of Obesity: Obesogen HypothesisHypothesis

• We hypothesize that environmental agents act during development to– Control adipose tissue development

• Via an increase the number of fat cells

– Control food intake and metabolism• Via effects on pancreas, adipose tissue, liver, GI tract, brain and/or muscle

thereby altering the programming of the obesity “set-point” or sensitivity for developing obesity later in life

Meta-analysis of Smoking During Pregnancy vs. Overweight

Oken et al, Int J Obes, 2008

Increased adipogenesis

Reduction of sensitivity to insulin

Increased food efficiency (high fat diet)

Reduction of physical activity

Glucose intolerance

Increased b.w and fat mass

Atrophy and apoptosis of pancreatic islets

PrenatalPrenatal//PerinataPerinatal l Nicotine Nicotine ExposurExposuree

Developmental Exposure to DES and Weight GainDevelopmental Exposure to DES and Weight Gain Proof of Principle Proof of Principle

Exposure of CD-1 mice to DES for 5 days at birth results in increased weight gain starting at puberty in female mice. No change in food intake or exercise. Newbold et al.

0.05.010.015.02025.030.035040.0450500

1 Month 4 Month

ControlDES

Obesogens – Just the Tip of the Iceberg?

Tributyl Tin

EstradiolPFOA Genistein Lead

DESPhthalates Nicotine Air Pollution (PM2.5)

Benzo[a]pyrene (PAH)Monosodium Glutamate

Bisphenol APBDEs PCBs?

Organophosphate Pesticides (Parathion, Diazinon, Chlorpyrifos)

Fructose?

Environmental Exposures and Diabetes

• Bisphenol A, DES (estrogens)

• POPS (PCBS, dioxins, HCB, DDE)• Organochlorine pesticides

– Oxychlordane– Aldrin– Nonachlor

• Arsenic• Organophosphate pesticides

– Malathion– Diazinon

• Air pollution

• Nitrates/ nitrite/ nitroso compounds (E/I)

• Air pollutants (ozone, sulphates)• PCBs (E/I)

• Phthalates (E/I)• Mercury, Cadmium (E/I)

• Trichloroethylene (I)

• Dioxin (E/I)

Endocrine (E) Immune (I)

Type 2 Diabetes Type 1 Diabetes

Public Health Implications of Obesogen Hypothesis?Public Health Implications of Obesogen Hypothesis?

• Hypothesis changes focus from

– intervention in adults to prevention during development

– from genetics to gene-environment interactions

• Changes the focus to prevention

– Focus on pregnancy, early childhood and puberty as sensitive periods

– Reduced exposures to environmental agents during development

– Improved nutrition during development

THE END…THE END…

or just the beginning?or just the beginning?